MicroRNA-binding site SNPs in deregulated genes are associated with clinical outcome of non-small cell lung cancer
MicroRNA-binding site SNPs in deregulated genes are associated with clinical outcome of non-small cell lung cancer
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失调基因中的 MicroRNA 结合位点 SNP 与非小细胞肺癌的临床结果相关。
DOI：
10.1016/j.lungcan.2014.06.010
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发表时间：
2014-09-01
期刊：
影响因子：
5.3
通讯作者：
Shu, Yongqian
中科院分区：
文献类型：
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作者：
Xu, Jiali;Tian, Shengwang;Shu, Yongqian
背景：癌症相关基因3'-非翻译区域的单核苷酸多态性（snp）可能影响microrna的调控，并影响癌症患者的预后。方法：我们使用公共数据库鉴定非小细胞肺癌（NSCLC）中解除调控基因mirna结合位点内的snp。576例NSCLC患者共纳入10个基因的13个snp，并通过SNaP-shot法进行基因分型。通过Cox回归和logistic回归评估snp、总生存期（OS）和化疗反应之间的关系。然后我们检查了显著多态性的功能。结果：两个snp （TYMS rs2790和MICA rs9266825）与OS有显著相关性。在综合分析中，不良基因座数量的增加与预后不良相关（趋势P < 0.001），与携带0-1个不良基因座的患者相比，携带2-3个不良基因座的患者死亡风险增加1.61倍（95%置信区间：1.20-2.15）。在296例未手术的晚期NSCLC患者中观察到snp对铂基化疗反应的显著影响：rs2790， rs4246215和rs1882。利用HapMap的mRNA表达数据进一步分析表明，这些显著位点（FEN1 rs4246215、HDAC2 rs11391、MICA rs1882和rs9266825）与宿主基因表达密切相关。对TYMS rs2790进行体外功能研究。荧光素酶检测显示，rs2790 G等位基因的表达水平低于a等位基因，hsa-miR-1248对TYMS基因的调节有影响。结论：我们的数据表明，去调控基因中的mirna结合位点snp可能作为非小细胞肺癌临床预后的候选预后标志物。2014爱思唯尔爱尔兰有限公司版权所有。
Background: Single-nucleotide polymorphisms (SNPs) in 3'-untranslated regions of cancer-related genes might affect regulation by microRNAs and contribute to cancer patients' outcome.Methods: We used public databases to identify SNPs within miRNA-binding sites in deregulated genes in non-small cell lung cancer (NSCLC). A total of 13 SNPs in 10 genes were included and genotyped by SNaP-shot assay in 576 NSCLC patients. Associations between SNPs, overall survival (OS) and chemotherapy response were evaluated by Cox regression and logistic regression. We then examined the functionality of the significant polymorphisms.Results: Two SNPs (TYMS rs2790 and MICA rs9266825) were significantly associated with OS. In the combined analysis, an increasing number of unfavorable loci was associated with a poorer prognosis (P for trend < 0.001) and patients having 2-3 unfavorable loci had a 1.61-fold elevated risk of death (95% confidence interval: 1.20-2.15), compared with those carrying 0-1 unfavorable loci. A significant effect of SNPs on platinum-based chemotherapy response was observed among 296 advanced NSCLC patients without surgical operation: rs2790, rs4246215 and rs1882. Further analysis using mRNA expression data from the HapMap suggested that these significant loci (FEN1 rs4246215, HDAC2 rs11391, MICA rs1882 and rs9266825) were closely associated with host genes expression. In vitro functional study for TYMS rs2790 was carried out. Luciferase assay showed a lower expression level for rs2790 G allele as compared with A allele, and the hsa-miR-1248 had,an effect on modulation of TYMS gene.Conclusion: Our data indicate that miRNA-binding site SNPs in deregulated genes may serve as candidate prognostic markers of NSCLC clinical outcome. (C) 2014 Elsevier Ireland Ltd. All rights reserved.